Abstract: While strategies to repair damaged skin have advanced, the ability to regenerate hair follicles and their associated glands has lagged behind. Our research has identified a genetic mechanism that regulates the size of the hair follicle and the size and shape of the hair shaft it produces. This mechanism acts in the dermal papilla (DP) of the hair follicle and promotes a switch from production of smaller to larger hairs. Among the targets of this transcription factor are a melanocortin receptor and components of associated signal transduction pathways. The hypothesis, supported by this observation and prior work, is that signaling through melanocortin receptors (Mcrs) in the DP of the hair follicle re-sets the signaling environment to specify hair follicle size and hair type. To test this hypothesis, we will analyze the hair of mice harboring loss of function alleles of the melanocortin receptors Mc3r and Mc5r that are expressed in the DP. We will use cell-type specific restoration of Mc3r function to confirm that any observed effects are direct. The relative importance of Mcr signaling to the hair type re- specification achieved by altering Sox2 function in the DP will be evaluated. Mcrs signal through several signal transduction pathways. Designer Receptor Exclusively Activated by Designer Drugs (DREADDs), synthetic GPCRs coupled to distinct downstream transduction pathways and activated only by exogenous drugs, will be used to test these pathways. Cre-dependent alleles will limit their expression to the DP and synthetic ligands will control the timing and level of activation. RNAseq on DP cells purified from these mice will be used to characterize gene expression differences in response to manipulation of Mcr and G-protein signaling. This work is expected to identify a novel pathway that regulates inductive signaling between dermal papilla and hair follicle keratinocytes to specify hair size and shape. It will have applications in efforts to restore hair production in skin damaged by trauma or disease. The hair follicle also serves as a model system to understand conserved signaling pathway interactions that mediate organogenesis and the results are expected to have application in regenerative medicine approaches to other organs as well.